Chronic renal allograft damage is one of the most important unsolved problems in transplantation. The overall goal of these studies is to improve long-term renal allograft survival via development of gene classifiers that predict a future decline in renal allograft function and eventual graft loss. Our central hypothesis is the inflammatory gene expression suggestive of persistent cellular alloreactivity is the primary process responsible for declining GFR from 1 to 5 years after transplantation. We also hypothesize that gene expression studies will help characterize this process in detail and suggest targets for therapeutic intervention. At 1 year, 80% of renal allografts show normal histology or fibrosis alone. However, 20% of these grafts will develop a decline in GFR (-3 ml/min/yr) and are at increased risk for late graft loss. Our Preliminary Data suggests that the expression of genes associated with inflammation and graft-infiltrating T cells, B cells and macrophages are associated with declining GFR. In Specific Aim 1, we will validate these preliminary findings in a larger retrospective study using 160 renal allografts for which we already have a 1 year biopsy and subsequent follow up (50 with declining GFR and 110 stable). The second most common finding on 1 year protocol biopsies is fibrosis associated with inflammation (graft infiltrating cells) which carries a risk of graft loss or decline in function of >50% by 5 years. In Specific Aim 2, we will demonstrate in another retrospective study of grafts already banked that gene expression differences on 1 year protocol biopsies with fibrosis and overt cellular infiltrate predict which grafts will respond to therapy (2A) and which grafts will subsequently return to normal histology and stable GFR between years 2-5 (2B). Finally, we recognize that data from our single-center may not be generalizable to other centers. In Specific Aim 3, we will validate the gene expression signatures associated with progression and response to therapy that are present in 1 year protocol biopsy in a large, prospective, multicenter study (Mayo Clinic, AZ; Mayo Clinic, FL; Henry Ford Hospital, Detroit, Ml and Mayo Clinic, Rochester). Given the lack of data regarding the actual mechanisms of chronic injury, we believe that these studies will provide significant clarification of current concepts of chronic renal allograft damage. We also believe that these studies will lead to the development of innovative management protocols after transplantation that will improve long-term graft survival. RELEVANCE: The reasons why kidney transplants do not last indefinitely is unclear. We study well-functioning kidneys early after transplant using a sensitive technique called gene expression which can reflects what is going wrong in the kidney. Gene expression appears to identify kidneys that will lose function later, sheds light on the causes of kidney transplant damage and may lead to new therapy that will help transplants last longer.